UPDATE ON BURNING MOUTH SYNDROME O PATIENT … · 14(4):275-291 (2003) Crit Rev Oral Biol Med 275 (I) Introduction Burning Mouth Syndrome (BMS) is a chronic pain syn- drome that mainly

14(4):275-291 (2003) Crit Rev Oral Biol Med 275

(I) Introduction

Burning Mouth Syndrome (BMS) is a chronic pain syn-drome that mainly affects middle-aged/old women with

hormonal changes or psychological disorders (Gorsky et al.,1987, 1991; Grushka, 1987). This condition is probably of mul-tifactorial origin, often idiopathic, and its etiopathogenesisremains largely obscure. BMS represents a disorder with avery poor prognosis in terms of quality of life, and thepatient's lifestyle may worsen when psychological dysfunc-tions occur (Lamey and Lamb, 1988; Bergdahl et al., 1995b;Jerlang, 1997). As a result, BMS subjects continue to be highconsumers of healthcare resources (Yontchev and Carlsson,1992; Haberland et al., 1999).

Despite the fact that a voluminous amount has been pub-lished in this field, a universally accepted definition of this syn-drome is still lacking. Various synonyms—such as stomatopy-rosis, glossopyrosis, stomatodynia, glossodynia, sore mouth,sore tongue, and oral dysesthesia—have been interchangeablyadopted to emphasize the quality and/or the location of painin the oral cavity. In this syndrome, however, pain representsthe main symptom within a variety of chronic oral complaints.Thus, BMS appears to be the most appropriate terminology(van der Waal, 1990), and only this term will be used in thepresent dissertation.

In the last decade, the International Association for the

Study of Pain (IASP) has identified BMS as a "distinctive noso-logical entity" characterized by "unremitting oral burning orsimilar pain in the absence of detectable oral mucosa changes"(Merskey and Bugduk, 1994). The state of knowledge on BMSwas presented at the 3rd World Workshop of Oral Medicine(Grushka and Epstein, 1998), and, very recently, different selec-tive review papers focusing on specific BMS issues have beenpublished (Fraikin et al., 1999; Marbach, 1999; Muzyka and DeRossi, 1999; Rhodus et al., 2000; Botha et al., 2001; Zakrzewskaet al., 2001).

Despite this large body of knowledge, some issues on BMSare still debated, and they present a challenge for bothresearchers and clinicians. What generates a major dilemma isthat BMS is defined by symptoms that can potentially arisefrom numerous different local/systemic pathologies, some ofwhich can be clearly identified and managed, and others thatelude diagnosis and, thus, hamper management. Very recently,several authors (Grinspan et al., 1995; Zakrzewska, 1995;Bergdahl and Bergdahl, 1999; Sardella and Carrassi, 2001;Zakrzewska et al., 2001) have focused their efforts on establish-ing whether BMS should be considered as a distinct "syn-drome", or if it mostly represents a "symptom disruption" for alarge number of conditions arising from a wide array ofpathologies (hormonal changes, nutritional deficiency, etc.).They have proposed the lack of local/systemic factors as inclu-

UPDATE ON BURNING MOUTH SYNDROME:OVERVIEW AND PATIENT MANAGEMENT

A. Scala*L. ChecchiM. MontevecchiI. Marini

Department of Oral Surgery, School of Dentistry, University of Bologna, Via San Vitale 59, 40125 Bologna, Italy; *corresponding author, [email protected]

M.A. Giamberardino

Department of Medicine and Science of Ageing, University of Chieti, Via dei Vestini, 66013 Chieti, Italy

ABSTRACT: Burning Mouth Syndrome (BMS) is a chronic pain syndrome that mainly affects middle-aged/old women withhormonal changes or psychological disorders. This condition is probably of multifactorial origin, often idiopathic, and itsetiopathogenesis remains largely enigmatic. The present paper discusses several aspects of BMS, updates current knowledge,and provides guidelines for patient management. There is no consensus on the diagnosis and classification of BMS. Theetiopathogenesis seems to be complex and in a large number of patients probably involves interactions among local, systemic,and/or psychogenic factors. In the remaining cases, new interesting associations have recently emerged between BMS andeither peripheral nerve damage or dopaminergic system disorders, emphasizing the neuropathic background in BMS. Based onthese recent data, we have introduced the concepts of "primary" (idiopathic) and "secondary" (resulting from identified precip-itating factors) BMS, since this allows for a more systematic approach to patient management. The latter starts with a differen-tial diagnosis based on the exclusion of both other orofacial chronic pain conditions and painful oral diseases exhibiting muco-sal lesions. However, the occurrence of overlapping/overwhelming oral mucosal pathologies, such as infections, may cause dif-ficulties in the diagnosis ("complicated BMS"). BMS treatment is still unsatisfactory, and there is no definitive cure. As a result,a multidisciplinary approach is required to bring the condition under better control. Importantly, BMS patients should beoffered regular follow-up during the symptomatic periods and psychological support for alleviating the psychogenic compo-nent of the pain. More research is necessary to confirm the association between BMS and systemic disorders, as well as to inves-tigate possible pathogenic mechanisms involving potential nerve damage. If this goal is to be achieved, a uniform definition ofBMS and strict criteria for its classification are mandatory.

Key words. Burning mouth syndrome, stomatodynia, oral dysesthesia, neuropathic pain, pain management.

sion criteria for a "true BMS", and assumed that all the othertypes of "unremitting oral burning" correlated to differentpathologies may be one symptom within the clinical spectrumof such a group of pathologies (Woda and Pionchon, 1999).

Burning pain without mucosal or skin lesions, however, rep-resents the typical symptom of chronic neuropathic pain condi-tions resulting from nerve damage, and in recent years a neuro-pathic basis of BMS has been better identified through the use ofmore sensitive diagnostic techniques (Svensson et al., 1993;Jaaskelainen et al., 1997, 2001; Gao et al., 2000; Forssell et al., 2002).This new evidence, in increasingly larger groups of BMS sub-jects, suggests a common background of neuropathy in thepathogenesis of this syndrome. As a result, it seems more appro-priate to recognize two clinical forms of BMS: "Primary BMS", oressential/idiopathic BMS for which organic local/systemic caus-es cannot be identified; and "Secondary BMS", resulting fromlocal/systemic pathological conditions and thus potentially sen-sitive to etiology-directed therapy. According to these criteria,"idiopathic" BMS as well as the "secondary" form may representtwo distinctive subgroups of the same "pathological entity".

The purpose of this review is to present an update ofknowledge on BMS. Difficulties arose in our attempt to com-pare data on BMS from different studies, because there wasconsiderable variability in the diagnostic criteria used in thesestudies. However, a detailed clinical description of this syn-drome will be provided and the most controversial aspects(etiopathogenesis and classification) discussed. Finally, guide-lines for effective patient management will also be suggested.

(II) EpidemiologyBMS is a disorder typically observed in middle-aged and elder-ly subjects with an age range from 38 to 78 years (Basker et al.,1978; Lamey and Lamb, 1988; Tammiala-Salonen et al., 1993;Bergdahl and Bergdahl, 1999). Occurrence below the age of 30is rare (van der Waal, 1990), and the female-to-male ratio isabout 7:1 (Basker et al., 1978; Grushka, 1987; Lipton et al., 1993;Tammiala-Salonen et al., 1993; Bergdahl and Bergdahl, 1999).

Adequate numbers of studies reporting appropriate epi-demiological samplings of BMS patients are still lacking. Thus,BMS prevalence appears to be widely inaccurately estimated. At

first, there was an over-diagnosis of BMS patients in the investi-gated populations. Previous studies, in fact, reported various andextremely large ranges of BMS prevalence, from 0.7% to 4.6%(Grushka and Sessle, 1991; Lipton et al., 1993; Hakeberg et al.,1997; Bergdahl and Bergdahl, 1999) or more (Tammiala-Salonenet al., 1993). This variability was likely due to the various criteriaused for BMS diagnosis. For instance, when BMS was identifiedonly on the basis of a prolonged burning sensation of the oralmucosa, a prevalence of 14.8% was estimated (Tammiala-Salonenet al., 1993). However, when diagnosis was arrived at by the useof more correct criteria (Bergdahl and Anneroth, 1993), BMSprevalence fell to 0.7%. At present, we have significant reasons tobelieve that this syndrome is more widespread than is estimatedaround the world. To appreciate the potential distribution of BMSin a population, one should note that a representative survey insubjects reporting orofacial pain in the United States estimatedthat about 1.3 million American adults were potentially affectedwith BMS (Lipton et al., 1993). Major demographic data, howev-er, are limited to studies from Northern Europe (Tammiala-Salonen et al., 1993; Thorstensson and Hugoson, 1996; Hakeberget al., 1997; Clifford et al., 1998; Bergdahl and Bergdahl, 1999),North America (Lipton et al., 1993; Riley et al., 1998; Haberland etal., 1999), South America (Grinspan et al., 1995), and South Africa(Maresky et al., 1993).

In conclusion, the use of an appropriate and consistentclassification system based on a universally accepted definitionof BMS and strict diagnostic criteria is mandatory, if the preva-lence of this syndrome is to be accurately estimated.

(III) Clinical FeaturesThe term "BMS" clinically describes a "variety of chronic oralsymptoms (Table 1) that often increase in intensity at the end ofeach day, and that seldom interfere with sleep" (Grushka, 1987;Gorsky et al., 1991). Accordingly, two specific clinical featuresdefine this syndrome: (1) a "symptomatic triad", whichincludes unremitting oral mucosal pain, dysgeusia, and xero-stomia; and (2) "no signs" of lesion(s) or other detectablechange(s) in the oral mucosa, even in the painful area(s). Full-blown syndrome is commonly observed in specific subgroupsof patients, such as peri-/post-menopausal women (Basker etal., 1978; Zachariasen, 1993; Ben Aryeh et al., 1996). In theremaining cases, "oligosymptomatic" (pain and dysgeusia orpain and xerostomia) or "monosymptomatic" (pain only) formsof BMS are the most frequent presentations.

More recently, increasing attention has been given to thealtered perception of sensory/chemosensory functions as wellas to the changes in the psychological profile of many BMSpatients. As a result, both disturbances should be included inthe clinical spectrum of BMS.

(A) PAIN

Oral pain represents the cardinal symptom of BMS. The type ofpain experienced by BMS patients is a prolonged "burning" sen-sation of the oral mucosa, similar in intensity to, but different inquality from, that associated with toothache (Grushka et al.,1987a). However, scalding, tingling, or numb feelings of the oralmucosa have also been reported (van der Waal, 1990). The onsetof oral pain is generally spontaneous and without any recogniz-able precipitating factors (Grushka, 1987; Tammiala-Salonen etal., 1993). However, some individuals with BMS relate the onsetof pain to previous events such as dental procedures (particular-ly dental extractions) or other diseases (Grushka, 1987;

276 Crit Rev Oral Biol Med 14(4):275-291 (2003)

TABLE 1Main Symptoms in Patientswith Burning Mouth Syndrome

Symptom Type(s) of Complaint(s)

Oral mucosal pain* Burning(main complaint) Scalding

TinglingNumb feeling

Dysgeusia* Persistent tasteAltered taste perception

Xerostomia* Dry mouthOthers Thirst

HeadacheTMJ painTenderness/pain in masticatory, neck,

shoulder, and suprahyoid muscles

* BMS symptomatic triad; TMJ = temporomandibular joint.

Tammiala-Salonen et al., 1993). Spontaneous remission of pain inBMS subjects has not been definitely demonstrated, although afew studies report relief without intervention (Mott et al., 1993).

To fulfill the diagnostic criteria for BMS (Bergdahl andAnneroth, 1993; Merskey and Bugduk, 1994), pain episodesmust occur continuously for at least 4-6 months. They may lastfor 12 years or more (van der Waal, 1990), with an averageduration of 3.4 years (Browning et al., 1987). Pain levels mayvary from mild to severe (Grushka et al., 1987a; Bergdahl et al.,1995a; Carlson et al., 2000; Pokupec-Gruden et al., 2000), butmoderate pain is the most frequent presentation (Basker et al.,1978; Jerlang, 1997). The mean severity of BMS pain has beenassessed at about 5-8 cm (or 50-80 mm) on a 10-cm (100-mm)Visual Analogue Scale (VAS) (Lamey and Lamb, 1988; Carlsonet al., 2000), where "0 cm (or 0 mm)" represents "no pain" and"10 cm (or 100 mm)" corresponds to "the worst possible pain".

The location of pain is not pathognomonic, and patientswith BMS may complain of burning sensations in many differ-ent sites, including extra-oral mucosa such as in the anogenitalregion (van der Waal, 1990). Oral pain is invariably bilateral,and more than one oral site may be affected (van der Waal,1990). The sites of predilection for pain are the tongue (especial-ly the tip or anterior two-thirds) (Grushka, 1987), the lower lip,and the hard palate (Dutree-Meulenberg et al., 1992; Tammiala-Salonen and Söderling, 1993; Eli et al., 1994; Grinspan et al., 1995;Svensson and Kaaber, 1995). The upper lip and mandibular-alveolar region may also be affected, whereas the buccal mucosaand the floor of the mouth are rarely involved (van der Waal,1990). As far as pain locations are concerned, some BMS subjectsmay experience other separate types of pain in association withoral burning. BMS patients, in fact, may suffer from headacheand pain in temporomandibular joint areas (Bergdahl et al.,1994), as well as tenderness/pain in masticatory, neck, shoulder,and suprahyoid muscles (Svensson and Kaaber, 1995).However, evidence of cause/effect relationships between oralsymptoms and head and neck pain has not yet been provided.

More than one clinical oral-pain pattern may occur in asso-ciation with local, systemic, and/or psychogenic disorders(Lamey and Lamb, 1988). On the basis of these patterns, it hasbeen suggested that BMS patients may be classified into threetypes (Lamey and Lewis, 1989). Type 1 BMS is characterized bya pain-free waking, with burning sensation developing in thelate morning, gradually increasing in severity during the day,and reaching its peak intensity by evening (Grushka, 1987;Grinspan et al., 1995). This type is linked to systemic disorderssuch as nutritional deficiency, diabetes, etc. (Lamey and Lamb,1988). Type 2 consists of continuous symptoms throughout theday, which, once started, often make falling asleep at night dif-ficult for many individuals (Grushka, 1987; Eli et al., 1994). Thissubgroup of patients often reports mood changes, alterations ineating habits, and a decreased desire to socialize, which seemto be due to an altered sleep pattern (Grushka, 1987; Grinspanet al., 1995). Common clinical findings in these subjects includeparotid gland hypofunction related to the use of anti-depres-sant drugs (Lamey et al., 2001). Finally, Type 3 BMS is charac-terized by intermittent symptoms with pain-free periods dur-ing the day. Frequently, these patients show anxiety and aller-gic reactions, particularly to food additives (Lamey et al., 1994).Overall, this sub-classification is not universally consideredessential for BMS patient management. However, it suggeststhe value of investigating possible local/systemic factors whichultimately lead to the neuropathic disturbance(s).

(B) DYSGEUSIA

In almost 70% of BMS patients, persistent taste disorders (dys-geusia) are also evident (Main and Basker, 1983; Grushka, 1987;Lamey and Lamb, 1988; Eli et al., 1994; Svensson and Kaaber,1995). The dysgeusic taste is most commonly bitter, metallic, orboth (Ship et al., 1995). Different alterations in taste perceptionappear at either threshold or suprathreshold levels (Grushka,1987; Grushka and Sessle, 1988). In fact, at threshold concen-trations, subjects with BMS may perceive sweet solutions assignificantly less intense, whereas the capacity to taste bothsweet and sour may increase at suprathreshold concentrations.Disorders in the sense of taste may be a sign of a disturbance ofsensory modalities at the level of small-diameter afferent fibers(Ship et al., 1995).

(C) XEROSTOMIAApproximately 46-67% of BMS patients complain of dry mouth(xerostomia) (Gorsky et al., 1987; Grushka, 1987; Bergdahl andBergdahl, 1999). In these individuals, the feeling of oral mucosaldryness generally reflects a subjective sensation (Bergdahl andBergdahl, 1999), rather than one objective symptom of salivarygland dysfunction. Subjective xerostomia in BMS patientsappears to be related to psychological problems such as depres-sion (Bergdahl et al., 1997). Strongest evidence, however, suggeststhat either feeling or evidence of dry mouth in these subjects ismore likely due to idiosyncratic side-effects from an extensiveabuse of anticholinergics, such as psychotropic drugs/medica-tions (Glass, 1989; Bergdahl and Bergdahl, 2000; Culhane andHodle, 2001) or antihistamines, and diuretics (Astor et al., 1999).

In a variable number of BMS patients complaining ofxerostomia, clear alterations in saliva quantity and/or qualitymay be detected (Hugoson and Thorstensson, 1991; Bergdahland Bergdahl, 1999). A reduction in salivary flow rate (hypo-salivation) is a common finding (Grushka et al., 1987b; Lameyand Lamb, 1988; Maresky et al., 1993; Johansson et al., 1994),whereas changes in salivary composition may vary. Protein(Ben Aryeh et al., 1996), potassium, and phosphate concentra-tions (Glick et al., 1976), in fact, have been found to be signifi-cantly higher in unstimulated saliva of some BMS subjects,whereas other patients have shown a decrease in total salivaryprotein concentrations (Basker et al., 1978; Tammiala-Salonenand Söderling, 1993). These findings suggest variability in sali-vary gland function disorders in some BMS subjects. As aresult, a variable number of these patients may suffer fromlack of lubrication and become more prone to develop infec-tions, because of reduced local host defenses (Jensen andBarkvoll, 1998; Chen and Samaranayake, 2000).

(D) SENSORY ANOMALIES

The frequent occurrence of dysgeusia in BMS subjects has ledto the assessment of sensory and chemosensory functions inthese patients. The perception of touch and temperature as wellas the pain tolerance are normal in several intra-oral and facialareas of some BMS subjects (Lamey et al., 1996), the only excep-tion being a significantly reduced perception of pain tolerancefollowing heat stimuli at the tip of the tongue (Grushka et al.,1987b). More recently, however, sensory anomalies and signifi-cantly increased pain thresholds have been shown through theuse of more sensitive methods, such as the argon laser stimula-tion (Svensson et al., 1993) and objective electrophysiologicalexamination of the trigeminal-facial system (Jaaskelainen et al.,1997; Gao et al., 2000). These findings suggest a possible change


in the peripheral and/or central nervous system in BMSpatients (Svensson et al., 1993; Jaaskelainen et al., 1997).

(E) ORAL FINDINGS

For the diagnostic criteria for BMS to be fulfilled (Bergdahl andAnneroth, 1993; Merskey and Bugduk, 1994), the clinical eval-uation of the oral mucosa must show complete absence oflesion(s) or other change(s), even in the painful areas (mainfinding).

BMS patients may show oral signs related to other associ-ated pathological conditions, such as salivary gland dysfunc-tion and/or masticatory system disorders (Bergdahl et al.,1994). Some patients may exhibit parafunctional habits such aslip and cheek biting, bruxism, tooth grinding and clenching,and, finally, tongue thrusting (Paterson et al., 1995), whereasothers may reveal parafunctional activity of lip pressure, liplicking, lip sucking, and mouth breathing (Lamey and Lamb,1994). A great many BMS subjects are denture-wearers (Gorskyet al., 1987; Grushka, 1987; Eli et al., 1994). Common findings inthis subgroup of patients include decreased daily usage of den-tures, reduced tongue space, incorrect placement of occlusaltable, and increased vertical dimension (Svensson and Kaaber,1995). In these individuals, a correlation between denturedesign errors and either local physical trauma or parafunction-al habits has also been suggested (Basker et al., 1978; Main andBasker, 1983; Gorsky et al., 1987; Lamey and Lamb, 1988).

(F) PSYCHOLOGICAL PROFILE

A strong psychological component in BMS has been clearlyidentified in the last decade (Maresky et al., 1993; Bergdahl etal., 1994, 1995a,b; Eli et al., 1994; Lamey et al., 1994; Rojo et al.,1994; Bergdahl, 1995; Grinspan et al., 1995; Svensson andKaaber, 1995; Van Houdenhove and Joostens, 1995; Humphriset al., 1996; Jerlang, 1997; Bergdahl and Bergdahl, 1999). It hasbeen suggested that somatic complaints from unfavorable life

experiences associated with chronic pain may influence bothindividual personality and mood changes (Jerlang, 1997).Many BMS patients, in fact, report one or more adverse lifeevents in their clinical/social history, such as difficult infancy,inadequate parenting, poor adaptation to school and/or work,family or marital strife, and financial problems (Jerlang, 1997).

Alterations in personality traits in BMS patients are com-parable with those observed in groups of subjects with otherchronic pain pathologies (Grushka et al., 1987a), such as atypi-cal facial pain, atypical odontalgia, and some forms of mastica-tory muscle and temporomandibular joint (TMJ) disorders(Woda and Pionchon, 1999). Mood changes consist of differentgrades of anxiety and depression (Demange et al., 1996; Trikkaset al., 1996; Jerlang, 1997; Bogetto et al., 1998; Carlson et al., 2000;Nicholson et al., 2000; Pokupec-Gruden et al., 2000), which oftenresult in an extremely poor quality of life. Other disruptionsinclude decreased aptitude to socialization, dizziness, psych-asthenia, excessive concern about health, too many sadthoughts, and reluctance to take the initiative (Bergdahl et al.,1995b). All these psychological disorders seem to be indepen-dent of symptom intensity (Bergdahl and Bergdahl, 1999), butappear to be mostly related to the prolonged period of pain anda long history of unsuccessful treatment (Bergdahl et al., 1995b).

The hypochondria and other phobias that may be associat-ed with BMS subjects represent a bad prognostic index. In par-ticular, these patients may experience higher levels of pain, anx-iety, and depression, especially when oral cancerphobia occurs(Grushka et al., 1987a; Lamey and Lamb, 1988; Jerlang, 1997).This concern may be particularly evident in those patientswhose family history is positive for head and neck cancer.

(IV) Etiopathogenesis and ClassificationThe etiopathogenesis of BMS is still unclear, and the issue hasgenerated considerable controversy in the literature. The mostdebated aspect is whether BMS should be definitively consid-


TABLE 2b

Principal Clinical Features in Different Idiopathic Orofacial Pain Conditions

Atypical Facial Pain Atypical Odontalgia Burning Mouth Idiopathic Facial(bone) (tooth) Syndrome (mucosa) Arthromyalgia (muscle, TMJa)

PainDescriptors Emotional, Varied Burning Spontaneous or during function or

mechanical, burning voluntary movementsIntensity Moderate to intense Moderate to intense Weak to intense Weak to intensePattern Continuous Continuous with Continuous Continuous with remissions

possible remissionLocalization Initially unilateral, Initially a single tooth, Bilateral, symmetrical Unilateral or bilateral

then bilateral then may spreadParoxysmal No No or little No NoPain during sleep No No Infrequent Uncommon but disturbed sleepOther associated Bone cavity, None Dysgeusia, xerostomia, TMJ functional limitations, tender-

signs/symptoms osteoporosis? thirst ness in masticatory/TMJ palpation, TMJ sounds, bruxism, parafunction

Neurological signs Dysesthesia, allodynia, Allodynia Sensory, chemo-sensory Allodynia (trigger point paresthesia anomalies in myofacial pain)

Psychologic profile Frequently altered Frequently altered Frequently altered Frequently altered

a TMJ = temporomandibular joint.b Reprinted with permission from Woda and Pionchon (1999).

ered either as a "distinctive nosological entity"or as a "symptom disruption" which has itsorigin in different pathologies (Grinspan et al.,1995; Zakrzewska, 1995; Bergdahl andBergdahl, 1999; Woda and Pionchon, 1999;Sardella and Carrassi, 2001; Zakrzewska et al.,2001). The crux of the problem is that BMSmay represent a complex of multiple diseaseswith overlapping symptoms. Consequently,dealing with a syndrome which is poorlydefined by symptom(s) without regard to eti-ology actually causes more problems relativeto diagnosis and management.

A recent trend in the field of pain hasbeen to attempt an accurate definition of dif-ferent poorly understood pain conditions andto standardize a classification scheme whichcould be of value for improving both clini-cal/laboratory research and patient manage-ment (Woda and Pionchon, 1999). In this con-text, it has been noted that specific chronicpain conditions, such as BMS, "atypical facialpain" and "atypical odontalgia", some "masti-catory muscle disorders", and "temporo-mandibular joint disorders" show commonclinical features (Table 2), such as similar painpatterns in the absence of clear etiologic evi-dence, and they are equally difficult to man-age. As a result, it has been proposed that allthese chronic pain disorders should be inclu-ded in a unified concept of idiopathic orofa-cial pain (Woda and Pionchon, 1999, 2000).According to this concept, the pain or burningof the oral mucosa caused by a known patho-logical process should be considered only asone symptom of this pathology, whereas thepain that cannot be attributed to any local orsystemic cause may be classified as "trueBMS" (or "stomatodynia").

The inclusion of stomatodynia (BMS) inthe above new classification is very cogent,but it would assume that little is known aboutthe mechanisms capable of generating oral mucosal burning orpain-like symptoms. Thus, if all BMS patients are grouped intothis proposed orofacial pain category, effective therapies formanaging the local or systemic etiological factors underlyingthis syndrome might be lost. The clinical features of BMSunderscore that the same specific symptomatic pattern (pain,dysgeusia, and/or xerostomia) in the absence of mucosallesions exists in BMS patients with identified etiologies as wellas in idiopathic cases. Thus, the above proposed BMS classifi-cation is likely to result in the exclusion of many patients, sincerecent pivotal studies, utilizing sophisticated diagnostic tech-niques, have drown attention to the neuropathic background inBMS (Jaaskelainen et al., 1997, 2001; Gao et al., 2000; Forssell etal., 2002).

From another point of view, clinical-epidemiological evi-dence reveals local/systemic factors in the majority of patientssuffering from BMS symptoms (Bergdahl and Anneroth, 1993;Ship et al., 1995; Zakrzewska, 1995; Cibirka et al., 1997; Muzykaand De Rossi, 1999). Elimination/treatment of these factors hasbeen shown to result in clinical improvement (Basker et al.,

1978; Main and Basker, 1983; Lamey et al., 1986; Gorsky et al.,1991; Forabosco et al., 1992). In this context, therapeutic failuresmight be explained by an underlying irreversible neuropathicdamage or disorder (Jaaskelainen et al., 2001) which can resultin the persistence of BMS even after removal of precipitatingfactor(s). Therefore, it seems more appropriate to classify thislarger subgroup of patients as affected with "secondary" BMSdue to local/systemic factor(s). It then follows that a smallersubgroup of BMS patients remains in whom it is not possible toidentify clear etiological factor(s) and who are, therefore, par-ticularly difficult to manage. Accordingly, BMS can be consid-ered a "specific spectrum" of chronic oral symptoms (Table 1,Fig. 1c), which has its origin in the activation of neuropathicmechanism(s) (Fig. 1b) from either unknown factor(s)("Primary BMS") or a wide array of pathologies ("SecondaryBMS") (Fig. 1a). In both subgroups, the etiologic role of psy-chogenic factors is still unclear (Figs. 1a, 1d).

(A) LOCAL FACTORSMany local conditions (infections, allergic reactions, galvanism,


Figure 1. Possible etiopathogenesis in Burning Mouth Syndrome (BMS). The action of orinteraction among one or more either unknown (x, y?) or well-identified (local, systemic,and/or maybe psychogenic) precipitation factors (a) might determine an either reversible( ) or irreversible ( ) neuropathic damage/disorder (b), such as peripheral nerve dam-age(s), dopaminergic system disorder(s), and/or other neurological alterations. Thesedisorders could result in BMS symptoms (c). The etiologic role of psychological distress isstill pending. However, long periods of chronic pain may also result in psychogenic dis-order(s) (d) , which can intensify BMS symptoms.

geographic tongue, dental treatment, etc.) have been proposedin the etiopathogenesis of BMS (Bergdahl and Anneroth, 1993;Ship et al., 1995; Zakrzewska, 1995; Cibirka et al., 1997; Muzykaand De Rossi, 1999). As far as local factors are concerned, how-ever, there is strong evidence only for local nerve trauma, oralparafunctional habits, and salivary gland dysfunction.

The frequent observation of taste changes and/or senso-ry/chemosensory dysfunctions in BMS patients has suggestedthat this syndrome could reflect a neuropathic disorder (Itkin,1968; Grushka and Sessle, 1991). In particular, a peripheral nerveinjury has been hypothesized (Grushka and Epstein, 1998), sincethe oral burning and the associated symptoms show a patternsimilar to that observed in some inflammatory neural conditions(neuritis) or regional nerve trauma (neuroma). In addition, somepatients with dysgeusia exhibit a loss of inhibitory interactionsbetween the central projection areas of the chorda tympani orglossopharyngeal taste nerves following peripheral injury toeither nerve (Lehman et al., 1995; Bartoshuk et al., 1996).

Several studies report that parafunctional habits areobserved in patients with BMS (Lamey and Lamb, 1988;Paterson et al., 1995). This parafunctional activity (tonguethrusting, bruxism, clenching) is significantly related to anxiety,and the activity most related to a high anxiety score seems to betooth clenching (Paterson et al., 1995). Parafunctional activityappears to be influenced by various exogenous factors, such asstressful life events, alcohol abuse, some personality character-istics, and psychiatric or neurological pathologies (Levigne andMontplaisir, 1995). The parafunction (especially night bruxism)is probably the result of an interaction between the limbic sys-tem and the motor system, but the dopaminergic system mightalso be involved (Kydd and Daly, 1985; Okeson et al., 1994;Gomez et al., 1999). Since several studies have provided evi-dence for some neurological alterations in BMS, it is conceiv-able that the parafunctional habits might result in neuropathicchanges that ultimately lead to BMS symptoms.

Salivary gland dysfunction might play a role in the onsetof this syndrome. For instance, radiation therapy, some sys-temic diseases, and a variety of pharmacologic agents(Niedermeier et al., 2000), known to be capable of inducing adecrease in salivary flow rate (Glass, 1989; Astor et al., 1999),have reportedly been associated with increased incidence ofBMS (Main and Basker, 1983; Jensen and Barkvoll, 1998). Aspreviously mentioned, BMS subjects may exhibit salivarygland dysfunction (Lamey and Lamb, 1988; Maresky et al.,1993). It has been suggested that, in some cases, BMS resultsfrom either a reduction in salivary output (volume) (Grushka,1987; Lamey and Lamb, 1988; Gorsky et al., 1991) or a decreasein the salivary components (glycoproteins) required for lubri-cating and protecting the oral mucosa (Grushka and Sessle,1991; Jensen and Barkvoll, 1998).

(B) SYSTEMIC FACTORSSeveral systemic factors may influence the prevalence, devel-opment, and severity of BMS symptoms (Bergdahl andAnneroth, 1993; Ship et al., 1995; Zakrzewska, 1995; Cibirka etal., 1997; Muzyka and De Rossi, 1999). The most significant sys-temic predisposing conditions for BMS are menopausal disor-ders, diabetes, and nutritional deficiencies.

There is a striking association between BMS and peri-/post-menopausal stages. Approximately 90% of women who attendhealthcare clinics for their BMS symptoms are peri-/post-menopausal women (Main and Basker, 1983; Gorsky et al.,

1987; Lamey and Lamb, 1988; Maresky et al., 1993; Zachariasen,1993). They report pain onset ranging from 3 years before to 12years after menopause (Grushka, 1987). Likewise, from 18% to33% of menopausal women exhibit BMS symptoms (Wardropet al., 1989; Ben Aryeh et al., 1996). In an attempt to understanda possible explanation for this association, investigators haveassessed several features of menopause in BMS women. Withinthis group, the duration and the type (e.g., natural, surgical,etc.) of menopause as well as the treatment-related features donot appear to play a pivotal role in either BMS development orseverity (Grushka, 1987). The most credited theory regardsmenopausal hormonal changes as a "master player" in BMSonset (Forabosco et al., 1992), although estrogen replacementtherapy (ERT) does not relieve pain in many cases (Basker et al.,1978; Wardrop et al., 1989). The variable response to ERT treat-ment may be due to either the presence/absence of the expres-sion of nuclear estrogen receptors in oral mucosa (Forabosco etal., 1992) or the possible activation of reversible/irreversibleneuropathic mechanism(s).

The association between BMS and nutritional deficiencieshas also been examined (Jacobs and Cavill, 1968; Brooke andSeganski, 1977; Lamey and Lamb, 1988). Occasionally, BMSpatients exhibit low levels of blood serum vitamins B1, B2(Hugoson and Thorstensson, 1991), and B6 (Dutree-Meulenberg et al., 1992), but a decrease in serum vitamin B12(Vucicevic-Boras et al., 2001) is the most common finding in thissubgroup of patients (Faccini, 1968; Main and Basker, 1983;Field et al., 1995). Vitamin B complex replacement therapy,however, often proves ineffective for pain relief (Hugoson andThorstensson, 1991; Dutree-Meulenberg et al., 1992). Otherminor findings of nutritional deficiency in BMS subjects mayinclude low levels of blood serum folic acid and iron (Dutree-Meulenberg et al., 1992), suggesting a possible role of some typeof anemia in the pathogenesis of this syndrome (Faccini, 1968;Jacobs and Cavill, 1968; Brooke and Seganski, 1977; Main andBasker, 1983; Schmitt et al., 1988; Lamey and Lewis, 1989).

The correlation between diabetes mellitus and BMS is stillcontroversial. It has been suggested that type II diabetes mellitusplays a role in BMS development (Brody et al., 1971; Lamey andLamb, 1988), and a link between the type of insulin used for thediabetes treatment and BMS has also been proposed (Basker etal., 1978). In contrast, other studies (Mott et al., 1993) report a lackof association between these two conditions (Lamey and Lewis,1989; Lamey and Lamb, 1994). A possible explanation for thiscontroversy may be that these diabetic patients were erroneous-ly classified as BMS. In fact, at the time of the above studies, alack of strict criteria for BMS diagnosis could have affected theselection of the patients. For instance, burning oral complaints indiabetic subjects, who are more prone to oral infections, are prob-ably caused by oral candidiasis (Tourne and Fricton, 1992).However, the lack of data cannot exclude the possibility that thealteration of pain thresholds in this BMS subgroup is related tothe neuropathy (Carrington et al., 2001), which is a common,though usually late, complication in type II diabetes mellitus.

(C) PSYCHOGENIC FACTORS

The long-held view, based on little or tenuous evidence, thatBMS is due to psychogenic/psychosomatic factors (Gorsky et al.,1991; Maresky et al., 1993; Bergdahl et al., 1994, 1995a,b; Lamey etal., 1994; Rojo et al., 1994; Bergdahl, 1995; Grinspan et al., 1995;Van Houdenhove and Joostens, 1995; Humphris et al., 1996) hasgenerally not been supported by scientific evidence, and the


reverse is the case. Many BMS patients exhibit high levels of anx-iety and depression as well as pain relief after suitable adminis-trations of psychotropic drugs/medications such as anti-depres-sants or benzodiazepines. However, there is increasing contro-versy as to whether depression and anxiety are primary(Pokupec-Gruden et al., 2000) or secondary events (Grushka andSessle, 1991) to the oral pain. It is noteworthy that psychologicaldysfunctions are common within a population of patients with awide variety of different types of chronic pain conditions. Forinstance, patients with a long history of treatment for atypicalodontalgia, atypical facial pain, and idiopathic facial arthromyal-gia have shown different grades of psychological disorders(Woda and Pionchon, 1999), suggesting that these disordersmight occur because of chronic pain. No association has beenfound between BMS development and stressful life events, evenin the cases with high levels of psychological distress (Eli et al.,1994). In addition, depression, anxiety, and somatic complaintssubsequent to emotional/psychosocial stresses may be absent inBMS patients, and there may be only a few disruptions in theirnormal activities due to oral burning (Carlson et al., 2000).Finally, BMS patients with psychological disorders frequentlyshow other precipitating factors, such as masticatory musculartensions, denture design errors, and parafunctional habits, all ofwhich are strictly associated with anxiety and depression inthese individuals (Paterson et al., 1995; Svensson and Kaaber,1995). These findings do not seem to support the hypothesis thatBMS is primarily a psychogenic disorder. On the contrary, theydraw attention to an overwhelming psychogenic component ofthe pain in the clinical spectrum of BMS (Nicholson et al., 2000),which may result from the patients' difficulty in coping withtheir suffering and/or emotional distress (Jerlang, 1997).

(D) NEUROPATHIC BACKGROUND INBMS ETIOPATHOGENESIS

Taste changes and/or sensory/chemosensory dysfunctions havebeen observed in many BMS patients, suggesting a neuropathicbasis for this syndrome (Itkin, 1968; Grushka et al., 1987b;Grushka and Sessle, 1991). Earlier studies provided only little ortenuous evidence of neuropathy in some BMS patients (Grushkaet al., 1987b; Grushka and Sessle, 1991). In the last decade, how-ever, the neuropathic basis of BMS has been underscored byfindings suggesting that there is an underlying disorder of the

autonomic innervations of the oral cavity in subjects with thissyndrome. It has been documented, in fact, that BMS patientsmay show: (1) abnormal perception of intensities in the pre-painrange and disturbances in the perception of non-nociceptive andnociceptive thermal stimuli (Svensson et al., 1993), (2) raisedtrigeminal nerve sensitivity and alterations in neuronal trans-mission (Gao et al., 2000), and (3) disturbances of the mucosalneurovascular microcirculatory system (Heckmann et al., 2001).These findings suggest peripheral alterations in the function ofthe sensory trigeminal nervous system in BMS. In further sup-port of these preliminary results, it should be noted that electro-physiological examination reveals an abnormal blink reflex (BR)in BMS subjects (Jaaskelainen et al., 1997). This reflex is underdopaminergic inhibitory control through the basal ganglia con-nection with the facial motor nuclei (Evinger et al., 1993;Jaaskelainen et al., 2001), and an abnormal blink reflex is also acommon finding in extra-pyramidal disorders such asParkinson's disease (Kimura, 1973) and facial dyskinesias(Berardelli et al., 1985). In these conditions, the abnormal reflex isthought to be due to a deficient dopaminergic striatal influenceon the brainstem nuclei (Evinger et al., 1993). These considera-tions, together with the very recent evidence of a decreaseddopaminergic inhibition in BMS subjects by Fluordopa-Pet scans(Jaaskelainen et al., 2001), lead one to suggest that BMS is a dis-order of the nigrostriatal dopaminergic system, which wouldprimarily affect the regulation of nociception of the trigeminalsystem, and thus cause a loss of sensory inhibition.

A more recent study (Forssell et al., 2002) provides furthersupport for the hypothesis that a neuropathic dysfunction isinvolved in BMS etiopathogenesis. These investigators usedquantitative sensory testing (QST) in addition to the BR record-ings in a large group of BMS patients. This study is very impor-tant, because it is the first attempt to evaluate the peripheral andcentral neural pathways of the trigeminal system in a large groupof BMS patients. There was considerable heterogeneity in thefindings, with some patients showing signs of large-fiber neu-ropathy, others of small-fiber neuropathy, and about one-fifth ofthe patients showing signs of increased excitability of the trigem-inal system (Table 3). In most patients, however, a link betweenthe electrophysiological signs of sensory disturbance and ananatomical alteration was not possible and, furthermore, was notstrictly confined to the site of the pain. Overall, the authors inter-


TABLE 3a

Neurological Alterations Detected via Electrophysiological Tests in Patients with Burning Mouth Syndrome

Neurological Alteration Electrophysiological Findings Reported Prevalence

Trigeminal neuropathy Brainstem pathology or peripheral trigeminal 10/52 cases (19%)neuropathy. In most of the cases, the BRb

abnormalities may represent sub-clinical changes in the trigeminal system

Increased excitability of the Increased excitability of the BR in the form 11/52 cases (21%), with two patients also trigeminal nervous system of a deficient habituation of the R2b showing signs of warm allodynia

component of the BRPure thin-fiber dysfunction Abnormality of one or more sensory thresholds, 35/46 cases (76%) with QSTb, with 33

indicating thin-fiber dysfunction patients also showing signs of hypoesthesia

a Reprinted with permission from Forssell et al. (2002).b BR = Blink Reflex; R2 = Late component of the BR response; QST = Quantitative Sensory Test.

pret their findings as suggestive of a generalized, possibly multi-level abnormality in the processing of somatosensory informa-tion in BMS, with electrophysiological evidence pointing to aperipheral neurogenic mechanism in the majority of patients.

(V) Considerations of Diagnostic CriteriaDiagnosis of BMS may be complex for three main reasons: (1)BMS is positively defined only by symptom(s) without regardto signs or etiologies; (2) the symptomatic triad rarely occurssimultaneously in one patient; and (3) overlapping or over-whelming stomatitis may confuse the clinical presentation. Asa result, clinicians can arrive at a diagnosis of BMS by match-ing specific details of the main complaint with clinical oralfindings that exclude oral mucosal changes, the only exceptionbeing the presence of stomatitis, which requires proper andprompt management. The search for identifiable causative fac-tors represents a next stage in BMS patient management, and itis essential for choice of the most appropriate therapy.

(A) INCLUSION DIAGNOSTIC CRITERIA

The first step in an initial diagnosis of BMS consists of a carefulanalysis of the symptom pattern experienced by each patient.The identification of full-blown forms of BMS is not problemat-ic, whereas the detection of either "oligosymptomatic" or "mono-symptomatic" variants is more complex. In any case, specificdetails of the main complaint (pain) represent the principal"inclusion symptom criteria" for BMS. These details includedaily bilateral oral burning (or pain-like sensation) and pain that:

(1) is experienced deep within the oral mucosa,(2) is unremitting for at least 4-6 months,(3) is continuous throughout all or almost all the day,(4) seldom interferes with sleep, and(5) never worsens, but may be relieved, by eating and drinking.

Further support may come from the identification of theother common complaints in BMS, which may be consideredadditional "inclusion symptomatic criteria", such as:

(6) the occurrence of other oral symptoms, such as dysgeusiaand/or xerostomia,

(7) the presence of sensory/chemo-sensory anomalies, and(8) the presence of mood changes and/or specific disrup-

tion(s) in patient personality traits.The pain pattern, which fulfills the inclusion symptomatic

criteria for BMS, must be compared with the oral mucosal sta-tus of patients. Here, the oral examination plays a critical rolefor the correct initial diagnosis of BMS. Patients with unremit-ting oral burning who exhibit one or more well-defined signsof oral mucosal pathology, such as white spot/lesion, erythe-ma, atrophy, erosion, ulcer, or other miscellaneous lesions,should be initially diagnosed as affected with stomatitis. Insubjects without signs of oral mucosal disease(s), an initialdiagnosis of BMS can be entertained.

(B) ORAL COMPLICATIONS

Possible oral complications in BMS may cause further prob-lems with regard to diagnosis and management. Salivarygland dysfunction and diabetes often make subjects more


TABLE 4Micro-organisms Found in Significantly HigherNumbers in Normal-looking Oral Mucosa ofPatients Complaining of Oral Burning

Micro-organism(s) References

Candida speciesa Brooke and Seganski, 1977Domb and Chole, 1981Gorsky et al., 1987, 1991Samaranayake et al., 1989

Enterobacterb Samaranayake et al., 1989Fusospirochetal bacteriab Katz et al., 1986Helicobacter pylorib Gall-Troselj et al., 2001Klebsiellab Samaranayake et al., 1989

a Fungi.b Bacteria.

TABLE 5Principal Hypersensitivity Reactions Reported in Subjects with Burning Mouth Syndrome

Contact Sensitivity due to Dental Materials Food Allergy

Allergens References Allergens References

Benzoyl peroxidea Dutree-Meulenberg et al., 1992 Chestnutsd Antico, 1996Cobalt chloridea Kaaber et al., 1979 Nicotinic acidc Haustein, 1988Mercuryb James et al., 1985 Octyl gallatec Pemberton et al., 1993

Albert, 1986 Peanutsd Whitley et al., 1991Methyl-methacrylatemonomera,b Kaaber et al., 1979

Ali et al., 1986 Propylene glycolc Lamey et al., 1987Lamey and Lamb, 1987van Joost et al., 1988) Sorbic acidc Haustein, 1988Dutree-Meulenberg et al., 1992

Nickel sulfate Kaaber et al., 1979Skoglund and Egelrud, 1991

Petrolatum cadmium sulphate Purello-D'Ambrosio et al., 2000

a Denture-base materials. c Ointment or cream preservatives.b Denture-filling materials. d Food.

prone to developing overlapping oral mucosal infections(Table 4), which may complicate the presentation of BMS.Furthermore, hypersensitive reactions (Table 5) to denture-base/dental-filling materials and food allergens in BMS sub-jects are more frequent than expected (Type 3 BMS) (Lamey etal., 1994), but do not seem to have any influence on the out-come of the syndrome (Virgili et al., 1996). In fact, the replace-ment of dental-filling materials (Bergdahl et al., 1994) mayrelieve the burning symptom in very few cases, whereas theremoval of the denture (Purello-D'Ambrosio et al., 2000) or dietmodification (avoiding food allergens) (Whitley et al., 1991)

often led to the clearing up of oral symptoms in a few days.The reported efficacy of denture removal in the relief of theoral complaint may be more likely due to the elimination ofdenture design errors or parafunctional habits (Paterson et al.,1995). Further complications in BMS may also result frominadequate oral hygiene due to oral pain in these patients(Perno, 2001). Thus, when mucosal erythema, ulcerative/ero-sive lesions, and atrophy, as well as gingivitis and periodonti-tis, are observed in BMS patients (Maresky et al., 1993), theyshould be considered as part of the clinical spectrum of a"complicated BMS".


Figure 2. Algorithm for the differential diagnosis of Burning Mouth Syndrome (BMS). (I) Algorithm for BMS diagnosis. (a) Anamnesis: BMS pain isinvariably bilateral and often relieved by eating and drinking; in contrast, the pain associated with inflammatory/immunomediated oral lesionsmay be unilateral and typically aggravated by food. (b) Oral mucosal examination plays a key role; lack of oral mucosal lesions points to BMSdiagnosis, whereas changes in the oral mucosa suggest other disease(s) or complicated BMS. (c) Initial diagnosis: A correct anamnesis associatedwith a careful oral examination may be sufficient for arriving at an initial diagnosis of BMS; both intra- and extra-oral pain levels are measuredthrough a linear Visual Analogue Scale (VAS). (d) Microbiological tests: The microbiological analysis of the oral mucosal areas where the pain islocalized may be effective for excluding possible bacterial or fungal invasions. Epicutaneous patch tests are strongly recommended in patients withtype 3 BMS. (II) Management of possible oral complication. Patients with oral mucosal lesions must be evaluated for their condition(s). In the caseof a painful white lesion removable with a spatula, a microbiological oral culture of a smear sample should be performed to exclude candidiasisor possible bacterial infections. Patients must be administered with topical/systemic antifungal or antibiotic therapy, if fungal or bacterial infections,respectively, are diagnosed. Subjects with painful erythematous lesions may require epicutaneous patch tests for possible allergy. When hypersen-sitive reactions to denture components are found, removal of the denture may lead to the clearing up of oral symptoms in a few days. Dental exam-ination is performed to exclude the presence of acute gingivitis, periodontitis, and/or other painful oral conditions. Appropriate oral hygiene inter-ventions and dental treatments may contribute to relieving suffering of patients. Erosive-ulcerative lesions, which do not disappear after 2 weeks,must be considered for a peri-lesional biopsy. When inflammatory/immunomediated diseases are diagnosed, appropriate treatment managementshould be provided. Persistence of the pain after proper treatments of such conditions is necessary for a diagnosis of complicated BMS.

(VI) Patient ManagementOwing to the large variety of associated factors, the protocol forBMS management is complex. An effective approach for thesepatients should be based on a strict collaboration among differ-ent oral medicine specialists. To begin with, it is very importantthat each patient be interviewed in an appropriately supportivemanner, so that the investigator can become familiar with thesubject (personal/familiar/social/medical history) as well asevaluate the organic component of his/her pain. Patient man-agement involves a differential diagnosis for BMS (Fig. 2) andthe discrimination between "Primary BMS" and "Secondary

BMS" based on the identification of possible etiologic factors forthe syndrome (Fig. 3). Patients with Secondary BMS can fall intospecific sub-categories according to the identified disorder(s)("patient stratification"), and, subsequently, they undergoappropriate therapy based on identified etiologies. The remain-ing cases (Primary BMS) will undergo proper pain control. Thissystematic approach to BMS has been reported to make patientmanagement more predictable and effective (Scala et al., 2003).

(A) DIFFERENTIAL DIAGNOSIS FOR BMSA correct clinical history associated with a careful examination


Figure 3. Algorithm for the final diagnosis of "Primary BMS" or "Secondary BMS". (a) Diagnostic procedure: This examination should befocused on the detection of local/systemic factors associated with the syndrome; dental/denture assessment may indicate a basis for potentialfunctional/parafunctional habits and/or dental design errors; sialometry and sialochemistry may provide diagnosis of hyposalivation and sali-vary composition changes, respectively; taste and sensory function tests may confirm (or exclude) neuropathic disorders; hematological examsmust include full blood cell count and differential, hematinic assays, evaluation of vitamin B status and folate, and blood glucose levels. (b) Finaldiagnosis: When the clinical examination shows one or more of the above factors in a BMS subject, the patient is considered as affected with"Associated BMS", as a result of local and/or systemic factors. Patients with normal local/systemic evaluation are considered to have"Idiopathic BMS". (c) Psychological evaluation: The goal is to detect the psychogenic pain component of the patients by means of proper struc-tured interviews and/or psychodynamic questionnaires.

of the oral mucosa may be sufficient to arrive at an initial diag-nosis of BMS, in the absence of overlapping/overwhelmingconditions (Fig. 2, part I). Details about quality, intensity, onset,occurrence, persistence, overall duration, evolution, and site(s)of pain symptoms are essential for the adequate assessment ofpain. Symptomatically, BMS must be differentiated from otherchronic pain conditions such as painful traumatic/inflammato-ry/immuno-mediated stomatitis or orofacial pain disorders(Table 2). The location of the main symptom (pain) in the oralmucosa excludes diseases such as atypical facial pain, atypicalodontalgia, and idiopathic facial arthromyalgia, which affectbones, teeth, muscles, and articulation, respectively. Specificdetails about pain, such as its localization, overall duration,and daily evolution, lead to a suspicion of BMS symptoms,rather than persistent oral mucosal lesions. In the latter group,in fact, pain is commonly unilateral, with some exceptions,such as diffuse oral infections and erosive lichen planus.However, in all these conditions, symptoms are characterizedby periods of remission and increased discomfort during eat-ing.

The suspicion of BMS symptoms can be reinforced bydetection of the other symptoms commonly associated withBMS, such as dry mouth, taste changes, and sensory anomalies.Further aid may come from the identification of possible exten-sive abuse of xerostomia-inducing drugs. Patients who fulfillthe inclusion symptomatic criteria for BMS (Fig. 2, part Ia)should be additionally evaluated for the potential psychogeniccomponent of their pain, with the use of psychometric instru-ments (Carlson et al., 2000), such as the McGill PainQuestionnaire (MPQ) (Melzack, 1987) and/or theMultidimensional Pain Inventory (MPI) (Kerns et al., 1985). Anobjective assessment of the pain should also be performed.Both pain intensity and evolution can be recorded and moni-tored via VAS.

Examination of the oral mucosa in these patients is crucial(Fig. 2, part Ib). BMS, in fact, must be differentiated from oralmucosal lesions (Bergdahl and Anneroth, 1993; Ship et al., 1995)that are accompanied by oral burning or pain-like symptoms,such as traumatic lesions, specific infections (e.g. candidiasis),and chronic erosive/ulcerative stomatitis (aphthous stomatitis,erosive lichen planus, pemphigoid, pemphigus, etc.).Neoplastic lesions must be excluded as well. The lack of oralmucosal pathology should lead one toward the diagnosis ofBMS (Fig. 2, part Ic).

Disorders that can potentially arise from local conditions

such as xerostomia should be explored. Xerostomia can alterthe oral microflora, resulting in, for example, an increase in thenumber of Candida species or other microbes (also withoutclear clinical manifestations) (Osaki et al., 2000). Therefore, oralswabs for fungal/bacterial microbiological culture are indeedrecommended, even if the painful areas of the oral mucosahave a normal appearance (Fig. 2, part Id). Allergy may alsooccur with or without oral manifestations (erythema). Thus,epicutaneous patch tests for both dental material and foodallergens are particularly indicated in those subjects whosemedical history reveals evidence of hypersensitivity.

In patients with oral mucosal lesions, one may be dealingwith either a complicated BMS or other pathologies (Fig. 2, partII). Persistence of pain after proper treatment of these mucosallesions is a "must" if the condition is to be considered a compli-cated BMS.

(B) DISCRIMINATION BETWEEN “PRIMARY” AND “SECONDARY” BMS

The procedure for differentiating "primary" from "secondary"BMS includes clinical/laboratory tests that are specificallymeant to identify local/systemic factors associated with thesyndrome (Fig. 3a). The evaluation of patients' masticatory sys-tems includes clinical assessment of the occlusal table of natur-al teeth, denture design, temporomandibular joint status, andmasticatory muscles (McNeill, 1997; Palla, 2001). Specific func-tional/parafunctional habits and salivary changes should becarefully recorded. Salivary flow rates below 0.1 mL/min forunstimulated whole saliva or 0.7 mL/min for stimulated wholesaliva would suggest a condition of hyposalivation (Navazesh,1993). Specific alterations in salivary composition can be detect-ed by sialochemistry (Tammiala-Salonen and Söderling, 1993).The objective evaluation of taste disturbances can be obtainedby the whole-mouth test of gustatory function (Ahne et al.,2000). This test is based on the identification of the four basictastes, with a maximum score of 24. Appropriate laboratorytests should be carried out if Secondary BMS due to systemicfactors is suspected. Nutritional deficiency, diabetes mellitus,and menopausal disorders are diagnosed through hematologi-cal assessment of nutritional status, blood glucose, and estro-gen/progesterone concentrations, respectively. If theclinical/laboratory examination unveils one or more of theselocal/systemic factors, such a patient should be considered asaffected with Secondary BMS, whereas a lack of these factorspoints to a final diagnosis of Primary BMS (Fig. 3b). The pres-


TABLE 6Structured Interview(s)/Psychodynamic Questionnaire(s) for the Psychological Evaluation of Patientswith Burning Mouth Syndrome

Psychometric Test Indication(s) Reference(s)

Hospital Anxiety and Depression Scale (HAD) Anxiety and depression Paterson et al., 1995Hamilton Rating Scale for Anxiety (HAM-A) Anxiety Maina et al., 2002Hamilton Rating Scale for Depression (HAM-D) Depression Maina et al., 2002Karolinska Scales of Personality (KSP) Alterations of personality traits Bergdahl, 1995

Bergdahl et al., 1995bPsychological Functioning Scale (PFS) Psychological functioning disability Bergdahl, 1995

Bergdahl et al., 1995bQuality of Life Scale (QLS) Quality of life Bergdahl et al., 1995b

ence of underlying psychological disorders can be revealed(Fig. 3c) by appropriate structured interviews and/or psycho-metric instruments (Table 6). The results of these tests mayhighlight both the nature and entity of the patients' psy-chogenic pain component.

(C) TREATMENT MANAGEMENT

Although a large variety of drugs, medications, and miscella-neous treatments has been proposed in BMS (Huang et al.,1996), the treatment management of this syndrome is still notsatisfactory, and there is no definitive cure (Botha et al., 2001;Zakrzewska et al., 2001). BMS patients have shown a goodresponse to long-term therapy with systemic regimens of anti-depressants (Maina et al., 2002) and anxiolytics (Grushka et al.,1998). In addition, some patients undergoing topical capsaicinadministration have experienced a partial or even completeremission of their pain (Epstein and Marcoe, 1994). However,the proposed pharmacological protocols have not consistentlyproved to be predictable and effective in all BMS subjects. Thelack of strict criteria for the selection of the groups of patientscan, in many cases, probably affect the response rate to thetreatment. Accordingly, the different factor(s) associated withSecondary BMS and the type(s) of psychological disorder(s)detected in these patients deserve major emphasis at the timeof treatment.

(a) Information for patients and psychological supportInitially, it is important to provide patients with information onthe nature of their condition and give reassurance, since BMSsubjects are likely to have consulted numerous specialists whostated that the mucosa was healthy and may thus be convincedthat their problems are imaginary (Lamey, 1998). Patients mustbe made aware, instead, that their pain is "real", the syndrome iscommon in middle-aged/elderly individuals, and is often linkedto some identified conditions. They must also be informed thatthe oral pain is not related to any form of cancer, that the treat-ment will be prolonged, and that not all the symptoms will def-initely disappear. Precautionary measures, such as abstainingfrom smoking and specific food allergens, should also be sug-gested. Drugs able to induce either BMS (Savino and Haushalter,1992; Culhane and Hodle, 2001) or xerostomia (Lamey et al.,2001) should be avoided as well. Some explanatory leaflets or

booklets may be helpful for this purpose (van der Ploeg et al.,1987). When evidence of a psychogenic pain component isdetected, specialists should also provide patients with adequatepsychological support. This preliminary counseling, in fact, canhave a great impact on the patients' attitude and may often resultin long-term beneficial effects (Bergdahl et al., 1995a).

(b) Causative therapy in "Secondary BMS"Subjects with Secondary BMS should initially be treated for theprecipitating factors of this disorder. Depending on the type ofsalivary dysfunction, xerostomia is controlled with seven-dayperiods of saliva substitutes or saliva-stimulating agents(Jensen and Barkvoll, 1998; Niedermeier et al., 2000). Saliva sub-stitutes have some properties similar to those of the salivaryglycoproteins (Johansson et al., 1994). Active stimulation of sali-vation may be obtained by means of chewing gums or sweets(containing sorbitol, not sucrose), whereas passive stimulationis achieved through specific cholinergic drugs (sialagogues),such as pilocarpine (Gorsky et al., 1991; Astor et al., 1999;Niedermeier et al., 2000). Pyridostigmine is of greater benefit,since it is longer-acting and associated with fewer side-effects.Parafunctional habits are treated by a biofeedback technique(Carlsson et al., 1975; Turk et al., 1996; Greco et al., 1997; Glaroset al., 1998, 2000) and/or proper bite (McNeill, 1997; Palla,2001). Muscular tensions/pain and temporomandibular jointmobilization are managed by means of physical relaxationtraining and physical therapy, respectively (McNeill, 1997;Marcus et al., 1998; Palla, 2001). Peri-/post-menopausal womenwith BMS should be referred to gynecologists. Proper adminis-tration of conjugated estrogens and medroxyprogesteroneacetate, in fact, may relieve oral symptoms in this subgroup ofBMS patients (Forabosco et al., 1992). Vitamin B complexreplacement therapy (pyridoxine, riboflavin, thiamine, etc.)may yield a good response (Lamey et al., 1986) in very fewcases of patients with nutritional deficiency (Hugoson andThorstensson, 1991).

As mentioned previously, the different types of responsesto etiology-directed therapy in "Secondary BMS" might berelated to the type(s) of neuropathic change(s) underlying thesyndrome. In non-responder cases, local and/or systemic pre-disposing factors may have caused an irreversible neuropathicdamage/disorder(s), and thus patients should be additionally


TABLE 7Drugs/Medications for Pain Control in Patients with Burning Mouth Syndrome

Topical Administration Systemic AdministrationMedication Dosage Reference(s) Drug Dosage Reference(s)

Capsaicina 3-4 times/day Epstein and Marcoe, 1994 Chlordizepoxidec 15-30 mg/day Gorsky et al., 1991Clonazepamb 0.5 mg/day Woda et al., 1998 Clonazepamc 0.25-3 mg/day Grushka et al., 1998

Diazepamc 2-30 mg/day Bessho et al., 1998

Amisulprided 50 mg/day Maina et al., 2002Paroxetined* 20 mg/day Maina et al., 2002Sertralined* 50-100 mg/day Van Houdenhove

and Joostens, 1995

a Cream. c Benzodiazepines (GABA-receptor agonist).b Tablet. d Tricyclic antidepressants (*selective serotonin re-uptake inhibitors).

treated with a therapy targeted to the neuropathic damage.Recently, a three- to four-week regimen of alpha-lipoic acid(ALA) has been claimed to provide a slight to decisive painreduction in BMS patients (Femiano et al., 2000; Femiano andScully, 2002). Based on the currently reported efficacy of ALAin neuronal damage (Tirosh et al., 1999), especially in diabeticneuropathy (Reljanovic et al., 1999; Ziegler et al., 1999), thisdrug might be particularly indicated in BMS subjects whoshow lack of response to etiology-directed therapy. Furtherinvestigation, however, is indeed mandatory for better defini-tion of the role of this drug in BMS.

(c) Supportive care in "Primary BMS": the control ofpain and associated symptoms

An effective approach to treatment management of patientswith Primary BMS should take into account that its etiology isunknown. It is thus inappropriate to conceive a definitive ther-apy for this condition; rather, one should consider "supportivecare in BMS" (Scala et al., 2003). The purpose of supportive careis to reduce the suffering of the patients, to bring their condi-tion under better control and improve the quality of life. Giventhe chronic nature of this painful syndrome, the treatment pro-cedures must particularly address the management of the mainsymptom (pain), which should be monitored through a VAS(Woda et al., 1998; Maina et al., 2002).

Many pharmacological agents, administered topically orsystemically, have been proposed to overcome the pain in BMS(Table 7). Low doses of capsaicin, applied 3 or 4 times topicallyon the area(s) where the pain is localized, appear to be quicklyeffective in alleviating the pain in BMS subjects (Epstein andMarcoe, 1994; Lauritano et al., 1998; Scala et al., 2003). However,there is a limited number of trials for corroborating its role inBMS pain control, probably because long treatment periodswith topical capsaicin are thought to result in depletion of sub-stance P (by causing C-fiber degeneration) (Simone and Ochoa,1991), with consequent loss of pharmacological effects.Consequently, administration of capsaicin for seven-day peri-ods, interspersed by periods of no treatment and the removalof capsaicin after each application, is recommended. Owing toits action (desensitization) on the C-nociceptor (Lynn, 1990),topical capsaicin may be indicated in pain control of BMS sub-jects with organic pain. Based on the reported new evidence ofchanges in peripheral autonomous innervation in BMS(Jaaskelainen et al., 1997), topical administration of other drugshas recently been considered. In particular, daily topical use ofclonazepam (! or " tablet applied 3 times each day for suck-ing) has shown partial to complete pain relief in most patientswith idiopathic BMS (Woda et al., 1998), suggesting a possiblelocal effect of this drug on gamma-amino-butyric-acid recep-tors (gaba-receptors) within the oral mucosa. However, in thisgroup of patients, the presence of high blood levels of clon-azepam might also indicate a systemic effect of this medicationin pain relief. Thus, the efficacy of clonazepam administrationshould be better documented and confirmed.

Patients with a stronger psychogenic component may beunresponsive to these medications. In these cases, the mosteffective pain management is the systemic administration ofmood-altering drugs (Gorsky et al., 1991). Long-term treatmentwith benzodiazepine-class drugs (anxiolytics) may be clinical-ly useful in BMS subjects (Bessho et al., 1998; Grushka et al.,1998). However, because of their target (central and peripheralgaba-receptors), benzodiazepines may be of special benefit in

BMS patients with anxiety. Other mood-altering drugs in BMSinclude anti-depressants. Low doses of tricyclic anti-depres-sants are characterized by an analgesic action, independent oftheir anti-depressive effect (Tourne and Fricton, 1992; Mott etal., 1993). Sertraline (Van Houdenhove and Joostens, 1995),paroxetine, and amisulpride are reported to be well-toleratedand effective after a four- to eight-week administration in BMSsubjects (Maina et al., 2002). Analgesic doses of anti-depressantsshould be adjusted according to the individual response andmay be particularly indicated in BMS patients with minordepression. Treatment with anti-depressive doses is indicatedin individuals with abnormal personality profiles, but it shouldbe undertaken in consultation with psychiatrists.

Patients who do not respond to any of the above treat-ments (resistant BMS) should undergo "cognitive" (Bergdahl etal., 1995a) or "cognitive/behavior" (Humphris et al., 1996) ther-apies by qualified psychotherapists, since they probably have,in their BMS spectrum, a strong and complex psychogeniccomponent of the pain. The purpose of psychodynamic thera-py is to allow each patient to understand the causes of his/hersymptoms. In this approach, patients are encouraged to explorethe possibility that their symptoms may serve as a form ofdefense against overwhelming emotional distress. Successfultreatment of BMS patients with combined psychotherapy andpsycho-pharmacotherapy has also been reported (VanHoudenhove and Joostens, 1995).

(d) Follow-upBecause of the debilitative nature of this syndrome, as well asthe frequently observed involvement of psychological disor-ders, BMS patients, particularly those resistant to treatment,should be offered regular follow-up from two to four times amonth during the symptomatic period. Each evaluation shouldinclude an analysis of pain levels, personality, psychologicalfunctioning, and quality of life. A personal interpretation of theevolving nature of the syndrome should be included in apatient diary.

(VII) ConclusionsBurning Mouth Syndrome remains a fascinating, though poor-ly understood, condition in the field of oral medicine. New evi-dence for the neuropathic basis of this syndrome is emerging.As a result, a subgroup of BMS cases may fall into the categoryof nigrostriatal dopaminergic disorder. In the remaining groupof patients, in whom there are clear precipitating local factors,BMS might be considered as a consequence of selective damage(trauma/chemo-mechanical irritation) to the nerve fibers of thetrigeminal nervous system. In these cases, however, it is notunlikely that a central nervous system disorder could be a keyfactor in the persistence of the syndrome.

Our opinion is that two new criteria may be useful in themanagement of BMS: (1) the occurrence of a "complicatedBMS", and (2) the distinction between "Primary BMS" and"Secondary BMS". Based on these distinctions, a caring sup-portive attitude, a correct patient stratification, and an appro-priate multidisciplinary approach will be the gold standardsfor a rational and beneficial application of current knowledge.

Research in this area, undertaken according to a variety ofapproaches, is needed. In-depth studies for a clear definition ofthe associations between BMS and systemic disorders based ona uniform definition, strict diagnostic criteria, and properpatient selection are also essential. In addition, evidence


involving the peripheral and/or central nervous system inBMS should be better documented and confirmed.

AcknowledgmentThe authors are grateful to Prof. Leonardo Vecchiet (Dean of the Departmentof Medicine and Aging, University of Chieti, Italy) for reading and com-menting on the manuscript.

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UPDATE ON BURNING MOUTH SYNDROME O PATIENT … · 14(4):275-291 (2003) Crit Rev Oral Biol Med 275 (I) Introduction Burning Mouth Syndrome (BMS) is a chronic pain syn- drome that mainly